Dataset Information

Exceptionally rare IDH1-mutant adult medulloblastoma with concurrent GNAS mutation revealed by in vivo magnetic resonance spectroscopy and deep sequencing

ABSTRACT: Exceptionally rare IDH1-mutant adult medulloblastoma with concurrent GNAS mutation revealed by in vivo magnetic resonance spectroscopy and deep sequencing

PROVIDER: PRJNA934923 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Similar Datasets

Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Project description:Urea cycle disorders represent a group of rare inborn errors of metabolism that lead to accumulation of ammonia, a toxic product of protein metabolism. Individuals with urea cycle disorders cannot metabolize the ammonia that accumulates due to enzyme deficiency. The symptoms of these disorders may present at birth, childhood or adulthood (milder deficiencies). There are currently eight enzyme deficiencies that constitute the range of inborn errors of ureagenesis. This project will focus on the most common enzyme disorder of the urea cycle, ornithine transcarbamylase deficiency, inherited as an X-linked trait. This project will study cognitive and motor dysfunction in patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non -invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies will range from ages 18-60 years and will be compared to an age-matched typically developed (TD) comparison group. For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.

Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adults. Based on transcriptome profile, MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) mutations have been described in several tumors, including gliomas, while in MB are rarely reported and not routinely investigated. By means of magnetic resonance spectroscopy (MRS), we unequivocally assessed the presence the oncometabolite D-2-hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutations, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also rarely described in MB. To the best of our knowledge, this is the first reported case of MB simultaneously harboring both mutations. Of note, tumor exhibited a heterogeneous phenotype with a tumor component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting co-existence of two different major tumor subclones. These findings drew attention to the need for a deeper genetic characterization of MB, in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, our results underlined the importance of performing MRS for the identification of IDH mutations in non-glial tumors. The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.

Dataset Information

Exceptionally rare IDH1-mutant adult medulloblastoma with concurrent GNAS mutation revealed by in vivo magnetic resonance spectroscopy and deep sequencing

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets